Crystalline hydrates of alkali metal salts of zinc trans-1 2-diaminocyclohexane-n n n&#39; n&#39;-tetraacetate

ABSTRACT

THE CRYSTALLINE HYDRATES OF THE SODIUM AND POTASSIUM SALTS OF THE ZINC CHELATE OF TRANS-1,2-DIAMINOCYCLOHEXANEN,N,N&#39;&#39;N&#39;&#39;-TETRAACETIC ACID (NA2ZNCDTA AND   K2ZNCDTA)

States Patent CRYSTALLINE HYDRATES OF ALKALI METAL SALTS OF ZINC 'TRANS-LZ-DIAMINOCYCLO- HEXANE-N,N,N,N'-TETRAACETATE Robert C.- ONeill, Newark, N.J., assignor to Cooper,

Tinsley Laboratories, Inc., Mystic, Conn.

No Drawing. Original application Jan. 3, 1967, Ser. No. 606,576, now Patent No. 3,501,576, dated Mar. 17, 1970. Divided and this application Nov. 13, 1969, Ser.

Int. Cl. C08f 3/06 U.S. Cl. 260-429.9 3 Claims ABSTRACT OF THE DISCLOSURE "The Crystalline hydrates of the sodium and potassium salts ofthe zinc chelate of trans-l,Z-diaminocyclohexane- N,N,N,N'-tetraacetic acid (Na ZnCDTA and K Z nCDTA where M represents sodium or potassium ions and n is a low number up to 4. The lower hydrates which are obtained, for example, when the compounds are evaporated to constant dryness are highly hygroscopic and tend to pickup moisture toform the tetrahydrate which is stable.

For thepurposes of this invention there is no preference r between the anhydrous salts and the various hydrates. As a'matiter of convenience their quantities are therefore betterdescribed by the amount of zinc present, i.e., the Zinc equivalent.

Na ZnCDTA-and K' ZnCDTA can be used orally and parenterally in doses to provide the equivalent of as much as 40 mg. of zinc daily per kilogram of body weight. Generally lower levels are preferred. The preferred route of administration is orally over a period of at least several days.

According to this invention, the Na ZnCD TA and K ZnCDTA can be associated with a carrier which can be either a solid m aterial or a sterile parenteral liquid. The compositions can take the form of tablets, powders, capsules,'or other dosage forms which are particularly useful for oral ingestion. Liquid diluents are employed in sterile'condition for parenteral use, that is, by injection. Such a medium can be asterile solvent such as water. The compositions can take the form of active material, namely, Na ZnCDTA 0!;KgZCDTA or both, admixed with solid dih1ents,table ting adjuyants, such as cornstarch,

lactose, talc, stearic acid, magnesium stearate, gums, or

Patented Feb. 22, 1972 the like. Any of the tableting materials used in pharmaceutical practice can be employed where there is no incompatibility with the Na ZnCDT-A and K ZnCD-TA. The material can be tableted with or without adjuvants. Alternatively Na ZnCDTA or K ZnCDTA or both with adjuvant material can be placed in the usual capsule or resorbable material such as the usual gelatine capsule and administered in that form. Na ZnCDTA and K ZnCDTA can also be put up into powder packets. Alternatively Na ZnCDTA or K ZncDTA or both can be prepared in the form of a suspension in a material in which Na ZnCDTA and K ZnCDTA are not soluble.

EXAMPLE 1 445.7 grams of trans-1,2 diaminocyclohexane-N,N,N', N-tetraacetic acid monohydrate (1.2 moles, 98% pure) were suspended in 360 ml. distilled water in a 4 liter beaker. 240 ml. of 10 N NaOH (2.4 moles) were added with stirring, after which 266 grams Zinc acetate dihydrate (1.2 moles, 99% pure) dissolved in 775 ml. distilled water were added with stirring.

The pH of the reaction mixture after complete addition of NaOH solution was 4.9 and was 3.9 after complete addition of the zinc acetate dihydrate solution. The resulting solution was evaporated overnight on a steam bath to yield a white crystalline magma which was then dried to constant weight at 62 C. (20 mm. Hg) in a vacuum oven containing alkali flakes as a desiccant. The resultant crude product (584 grams) was then recrystallized by dissolving it in a hot C.) solvent mixture consisting of 3900 ml. ethanol and 987 ml. distilled water, filtering with gravity, and chilling the clear solution thus obtained to 5 C. The copious crystalline precipitate which formed was collected by vacuum filtration, washed on the funnel with ethanol, and dried to constant weight at 68-75 C. under reduced pressure (0.1 mm. Hg). In this manner, 411.6 g. of product was obtained corresponding approximately to the monohydrate of disodium zinc trans 1,2 diaminocyclohexane-N,N,N',N-tetraacetate (hereinafter the recrystallized monohydrate will be described as the monohydrate of Example I).

A sample of the monohydrate of Example I was analyzed for carbon, hydrogen, nitrogen and zinc, as follows:

Percent H N Zn Found (average) 35.4 6.2 5.2 13.7 Calculated (as monohydrate) 35. 6 4.3 5. 9 13.8

crystalline.

EXAMPLE II A suspension of trans-l,2-diaminocyclohexane-N,N,N, N-tetraacetic acid monohydrate (93 g.,-'98% pure, 0.25 mole) in ml. of distilled water was prepared.

To this was added a solution of 33 g. (0.5 mole) of potassium hydroxide pellets (85.9% assay) in 50 ml. of distilled water. A clear solution resulted.- To this solution was added 55.4 g. (0.25 mole) of zinc acetate dihydrate (99% pure). After a brief period of stirring, a clear solution resulted. This was filtered and was then concentrated in vacuo to yield a crystalline residue. Recrystallizationof this residue from a mixture of methanol and acetone gave 90g. of colorless crystals. After having been dried to constant weight at room temperature under a vacuum of 0.1 mm., the compound Was subjected to analysis for zinc content. The calculated value, based on dipotassium zinc trans-1,2-diaminocyclohexane-N,N,N,N'-tetraacetate monohydrate, is 13.0%. Found: 12.9%. This free-flowing crystalline product, hereinafter referred to as the monohydrate of Example II, readily dissolved in water yielding a clear, colorless solution.

The compounds of the present invention are highly useful in solution form because of their high solubility in water and because aqueous solutions of these compounds are neutral. These properties are illustrated in Example III.

EXAMPLE HI Two grams of the monohydrate of Example I were added to 5 m1. of distilled water, yielding a clear solution. The following data were recorded:

Time Temperature pH minutes... 235 C. (ambient) do 280 C 6.5 6.5

The following examples are illustrative of typical dosage forms for administering the compounds of this invention to humans in the treatment of hypertension. The formulations are made by the usual procedures for making tablets, enteric coated tablets, gelatine capsules, packets and oral and parenteral solutions.

EXAMPLE IV [Oral tablets, equivalent to mg. zine] Parts by weight Example IV A IV B IV C Monohydrate of- Example I 182 91 Example II 193 96 Cum starch 100 96 98 Lactose 193 186 190 Gelatlne 20 20 20 Magnesium stearate 5 5 5 Parts by weight Exam le VI A v1 B v1 0 Monohydrate oi- Example I 362 181 Example II 385 192 Corn starch 115 127 The above ingredients are mixed and dispensed in gelatin capsules, 500 mg. per"capsule,' to provide a suitable dosage form for oral administration to humans in treatment of hypertension at a rate of 50 mg. zinc per capsule.

EXAMPLE VII.O RAL SOLUTION Example V11 A VII B VII 0 Monohydrate of- Example 1, grams 7.25 3. 12 Example 11, grams 7. 3. Sorbitol 70%, ml 10 10 10 Cyclamate, Sodium, mg 100 100 Methyl paraben, mg 1.8 1:8 1. 8 Propyl paraben, mg 0. 2 0. 2 0. 2 Flavor v Color Distilled deionized water to make up to The above ingredients are dissolved in water, as indicated, to form suitable solutions for oral administration to humans in treatment of hypertension at a rate of 5 0 mg. ofzincperSml. l H

EXAMPLE VIIL-PARENIERAL SOLUTIONS Example VIII A VIII B VIII 0 Monohydrate of Example I, mg"..- 182. 0 91 Monohydrate of Example II, mg.-- 193 96 Benzyl alcohol, mg 5.0 5. 0 5. 0 Sodium chloride, mg 5.0 5. 0 Potassium chloride, mg 5. 0

Potassium biphthalate, mg 8.0 8. 0 8. 0 Water for injection to make up to (ml)... 1.0 1. 0 '1. 0

References Cited UNITED STATES PATENTS 3,150,160 9/1964 Dexter 260-4299 X 3,240,701 3/1966 Furia 260429.9 X

FOREIGN PATENTS 785,024 10/ 1957 Great Britain 260-429 1 OTHER REFERENCES Pribil et al., Collection Cze'choslov. Chem; Conamum, vol. 18, pp. 43-52 1953). a I 1 V Day at al., Analytical Chemistry, vol. 37,pp. 1326-33 (1965). 91 Leonard et al., Proceedings of the Florida State Horti cultural Society, vol. 69, pp; 7279 (1956); TOBIAS E. LEVOW, Primary Examiner H. M. S. SNEED, Assistant Examiner US. Cl. X.R. 

